This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goals of this project is to systematically investigate how rigidity/flexibility varies among homologous structural domains of thermophilic and mesophilic proteins, to understand whether the rigidity/flexibility of thermophilic and mesophilic proteins correlate with their stability, and whether both properties are controlled by the same structural determinants. The method used in this study is a hierarchical physics based molecular modeling approach termed MD/FIRST (Mamonova, Phys. Biol. 2005), which combines the molecular dynamics (MD) simulations of a native structure protein in solution with a rigid cluster decomposition method FIRST based on the graph theory (Jacobs, Proteins: Struct., Funct., Genet. 2001). Using this approach we found that there are two groups of proteins. First one is characterized the salt bridge or ionic network. This network includes salt bridge triads Agr-Glu_Lys, Arg-Glu-Arg or salt bridges (like Arg-Glu) connected with hydrogen bonds. This ionic network accumulates alpha helixes and rigidifies the structure. The second groups can be characterized by the single salt bridges and h-bonds or small ionic clusters. Such difference in the network of salt bridges results in different flexibility of homologous protein. MD/FIRST approach allows for characterizing structural features in atomic detail that determine the rigidity/flexibility of a protein structure.